Apolipoprotein C-III Strongly Correlates with Activated Factor VII–Anti-Thrombin Complex: An Additional Link between Plasma Lipids and Coagulation

Abstract

Activated factor VII–anti-thrombin (FVIIa-AT) complex is a potential biomarker of pro-thrombotic diathesis reflecting FVIIa–tissue factor (TF) interaction and has been associated with mortality in patients with coronary artery disease (CAD). Previous data indicated plasma lipids as predictors of FVIIa-AT variability, and plasma lipoproteins as potential stimulators of the coagulation cascade. Our aim was to evaluate the relationships between FVIIa-AT plasma concentration and a broad apolipoprotein profile (including ApoA-I, ApoB, ApoC-III and ApoE). Within the framework of the observational Verona Heart Study, we selected 666 subjects (131 CAD-free and 535 CAD, 75.4% males, mean age: 61.1 ± 10.9 years) not taking anticoagulant drugs and for whom plasma samples were available for both FVIIa-AT assay and a complete lipid profile. Plasma concentration of FVIIa-AT levels significantly and directly correlated with total and high-density lipoprotein cholesterol, triglycerides, ApoA-I, ApoC-III and ApoE levels. ApoC-III showed the strongest correlation (R = 0.235, p = 7.7 × 10−10), confirmed in all the sub-group analyses (males/females and CAD/CAD-free). Only ApoC-III remained associated with FVIIa-AT plasma concentration, even after adjustment for sex, age, CAD diagnosis, body mass index, renal function, smoking status, lipid-lowering therapies and FVIIa levels. The APOC3 gene locus-tagging polymorphism rs964184, previously linked with cardiovascular risk and plasma lipids by genome-wide association studies, was associated with both ApoC-III and FVIIa-AT plasma concentration. Our results indicate a strong association between ApoC-III and FVIIa-AT levels, thereby suggesting that an increased ApoC-III concentration may identify subjects with a pro-thrombotic diathesis characterized by an enhanced TF-FVIIa interaction and activity.

The Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans

“…ApoC-III has also been shown to directly activate adhesion molecules and proinflammatory responses in monocytes and endothelial cells (Figure 1) (90,91). In addition, apoC-III levels have also been shown to strongly correlate with plasma levels of activated factor VII-anti-thrombin (FVIIa-AT) complex, a biomarker for increased predisposition to thrombotic events ( Figure 1); a strong association was found in both sexes, regardless of whether or not there had been a prior CAD event (92). Thus, apoC-III seems to link lipid metabolism and coagulation.…”

High Plasma Concentration of Apolipoprotein C-III Confers an Increased Risk of Cerebral Ischemic Events on Cardiovascular Patients Anticoagulated With Warfarin

“…Similarly, high levels of Apo CIII (but not other plasma lipids or apolipoproteins) were associated with a progressive increase in factor II coagulant activity (11). Apo CIII was also strongly associated with the activated FVII-antithrombin (FVIIa-AT) complex, which is an indirect marker of intravascular exposure of tissue factor (TF), thus providing suggestion for an Apo CIII-related activation of the extrinsic coagulation pathway (12). In a recent study involving 127 patients with venous thromboembolism and 299 controls, concentrations of Apo CI, CII, CIII and E were associated with several coagulation factors, including vitamin K-dependent factors, as well as factor XI, factor VIII, and von Willebrand factor levels (24).…”

“…A detailed description of the original study population has already been reported in a previous work (9). This observational study was performed within the framework of the Verona Heart Study (VHS), a regional survey that assessed cardiovascular risk factors in subjects with angiographic documentation of the state of their coronary vessels (9)(10)(11)(12). All the subjects in the VHS are required to have no history of any acute illness in the month preceding the enrollment.…”

“…Despite being treated with anticoagulants, a substantial number of these patients still develop cardioembolic complications and are exposed to the risk of ischemic stroke (10), increased factor II coagulant activity (11), and higher activated factor VII-antithrombin complex (FVIIa-AT) (12).…”

Apolipoprotein CIII predicts cardiovascular events in patients with coronary artery disease: a prospective observational study

“…ApoCIII inhibits lipoprotein lipase and hepatic VLDL uptake, and enhances hepatic VLDL secretion, by this increasing TRL levels [2][3][4][5][6][7]. Proinflammatory and prothrombotic effects of apoCIII have been described [8][9][10]. Furthermore, apoCIII modifies the effects of other lipoproteins: HDL particles containing apoCIII have been found to be associated with coronary artery disease (CAD) risk, while HDL particles without apoCIII were protective of CAD [11]; and the risk of CAD due to elevated LDL cholesterol appeared mainly to be due to LDL particles containing apoCIII [12], which may be mediated by the above-described mechanisms.…”